1. Field of the Invention
The desire to understand the mechanisms by which analgesics effectuate the reduction of pain and to develop new analgesics which are more effective and freer of side effects engendered the discovery of .beta.-endorphin and the smaller polypeptides leu-enkephalin and met-enkephalin. The first five amino acids of .beta.-endorphin are the five amino acids of met-enkephalin. There has been substantial activity in trying to develop modifications of leu-enkephalin and met-enkephalin to enhance their activity, since the activity of the smaller polypeptides is substantially lower than .beta.-endorphin.
Various techniques to inhibit degradation of the polypeptide have involved employing the artificial stereoisomer of one of the amino acids. Also, the carboxy end has been amidified and various amino acids have been added to the ends of the chain to enhance or modify activity.
In developing new polypeptide analgesics, there are a number of important considerations. A desirable analgesic will have relatively few amino acids, so as to be easily and economically synthesized in good yield. Furthermore, it is desirable that the polypeptide analgesic be easily administered and migrate to its natural binding site without substantial degradation. Otherwise, the polypeptide will have to be introduced adjacent to or at the site of binding to achieve the analgesic effect. Desirably, the potency should be substantially higher than available analgesics, while at the same time because of the reduced amount administered or because of its particular structure, the analgesic should be relatively free of undesirable side effects.
With the large number of amino acids available, and, the possibility for modification, such as acetylation and amidification, there are an astronomical number of possibilities of combining amino acids to achieve opioid potency. While leu-enkephalin and met-enkephalin have a tyrosine group which is analogous to the phenolic group of morphine, in view of the small size of morphine and analogous opioids, there were no directions as to how the enkephalins might be extended and, when extended, how their potency might be enhanced or activities modified, except for the .beta.-endorphin sequence. Therefore, while the possibility of having a polypeptide analgesic presented itself, the ability to determine an appropriate structure remained tantalizingly difficult.
2. Brief Description of the Prior Art
Cox et al. (1975) Life Sci. 16 1777 and Lowney et al. (1979) Life Sci. 24 2377 report two pituitary opioid peptides. Kangawa et al. (1979) Biochem. Biophys. Res. Comm. 86, 153 report an opioid peptide from porcine hypothalamus.